Tens of millions of people in the United States suffer from rheumatoid arthritis (RA) or a related disease. While arthritis results in significantly fewer deaths as compared to cancer and cardiovascular diseases, there is no other group of diseases that causes so much suffering in so many people for such a prolonged period of time. Because of the tendency for arthritis sufferers to become disabled and even permanently crippled, this group of diseases is extremely important both socially and economically. There is presently no satisfactory cure for rheumatoid arthritis because its cause is unknown. In addition, many of the therapeutic agents administered to alleviate pain and inflammation associated with the disease, such as disease-modifying antirheumatic drugs (DMARDs) and non- steroidal anti-inflammatory agents (NSAIDs), produce intolerable side effects.
The understanding of the RA disease process has been considerably enhanced by the application of molecular immunology techniques. It is now generally accepted that rheumatoid arthritis represents a multifactorial disease with environmental factors (infectious agents or toxins), genetic susceptibility, and immune or autoimmune responses playing inter-connected roles. After initiation of the disease process, it is believed that activated T cells and their products are responsible for the progressive destruction of articular cartilage and sub-chondral bone that is characteristic of rheumatoid arthritis.
Advances in the understanding of the immunopathogenesis of rheumatoid arthritis have been coupled with immunologic strategies for treatment. Immunologic approaches to the treatment of rheumatoid arthritis are important and desirable given the potential toxicities associated with most remittive therapy in use today and the continued poor prognosis of rheumatoid arthritis despite aggressive drug treatment. Monoclonal anti CD4 antibodies have been used in the treatment of rheumatoid arthritis (Reiter et al., Arthritis Rheum. 1991, 34, 525-536; Horneff et al., Arthritis Rheum. 1991, 34, 129-140; Herzog et al., J. Autoimmunity 1989, 2, 627-642; Goldberg et al., J. Autoimmunity 1991, 4, 617-630). In these studies, involving approximately 30 patients, objective and subjective improvement was noted in nearly all cases.
Another study employed chimeric monoclonal antibody to CD4 to treat 25 patients with refractory rheumatoid arthritis (Moreland et al., Arthritis Rheum. 1993, 36, 307-318) and again, some beneficial effects were observed.
Immunotherapeutic approaches have also included leukapheresis, (Karsh et al., Arthritis Rheum. 1981, 24, 867-873; Wallace et al., Arthritis Rheum. 1979, 22, 703-710) thoracic duct drainage (Paulus et al., Arthritis Rheum. 1977, 20, 1249-1262) and total node irradiation (Trentham et al., N. Engl. J. Med. 1981, 305, 976-982). All of these modalities have resulted in varying degrees of improvement, but all also have obvious drawbacks.
Patients with rheumatoid arthritis have also been treated with one or more 5 day infusion courses with monoclonal anti-CD5 coupled to Ricin-A chain (Strand et al., Arthritis Rheum. 1993, 36, 620-630). In this open-label trial, improvement rates were 50-68% at one month and 22-25% at 6 months (two clinical trials were included). All patients produced antibodies against the anti-CD5 conjugate and most experienced a transient decrease in CD3/CD5 positive T cells with recovery after 2-4 weeks.
Since cytokines also play important pathophysiologic roles in rheumatoid arthritis, research into therapeutics has also focused in this area. Tumor necrosis factor (TNF.alpha.) has received attention because it is consistently found in synovium of patients suffering from rheumatoid arthritis. In addition, anti-human TNF was demonstrated to prevent the development of arthritis in a transgenic human TNF.alpha. mouse model. Using chimeric (mouse-human) antibodies to TNF.alpha., twenty patients with active rheumatoid arthritis were treated (Elliott et al., Arthritis Rheum. 1993, 36, 1681-1690). Patients were given 20 mg/kg in divided doses weekly either over 2 or 4 weeks. They found overall improvement in the Ritchie Articular Index, joint count and C-reactive protein (CRP) levels, and reported no significant toxicity.
Immunization of patients having rheumatoid arthritis with autologous T cell lines established from cells obtained from RA synovial fluid (SF) and/or synovial tissue has also been shown to be of benefit in some patients (Kingsley and Verwilghen, Clin. Exp. Rheumatol. 1993, 11, S63-S64; Lohse et al., J. Autoimmunity 1993, 1, 121-130; vanLaar et al., J. Autoimmunity 1993, 6, 159-167).
Regarding treatment of humans with allogeneic mononuclear cells (MNC), patients receiving living-related renal transplants have been transfused with allogeneic blood in an attempt to limit the immune response. Similar therapies employing MNC have been applied in recurrent pregnancy loss since about 1981 based on the notion that the fetus represents an allogeneic "graft" and that women who have no demonstrable known cause for recurrent spontaneous abortion (RSA) are likely to be immunologically rejecting their fetuses. Since 1985, the inventor has immunized over 1500 women diagnosed as having RSA with MNC from their spouses. World-wide it is estimated that about 25,000 patients have received this treatment. No serious side effects from this treatment have been found.
Remission of rheumatoid arthritis occurs in about 70% of all pregnant women suffering from rheumatoid arthritis. Pregnancy induced remission was originally believed to be due to increased levels of cortisol but, clearly, it is not entirely due to hormonal effects. It has been observed that during pregnancy, women with rheumatoid arthritis who experience remission carry fetuses that are more disparate than similar to themselves with respect to class II alleles of the human leukocyte antigens HLA-DRB1, -DQA and -DQB (Nelson et al., N. Eng. J. Med. 1993, 329, 466-471). The immunologic mechanism(s) underlying this effect is not known; however, hypotheses include induction of suppressor mechanisms or displacement of arthritogenic peptides from maternal antigen presenting cells (APC) by fetal class II peptides thus subverting an arthritis-inducing immune response. Alternatively, maternal T cell recognition of specific allogeneic or fetal HLA-DR peptides may cause a switch from a predominantly proinflammatory response to one that is protective or suppressive.
While rheumatoid arthritis remains the prototype disease that improves during pregnancy, Multiple Sclerosis (MS) an autoimmune disease that affects about 160,000 women of child-bearing age in the U.S. (Davis and Maslow, Obstet. Gynecol. Surv. 1992, 47, 290-296) and that exhibits immunopathogenetic features similar to RA may be modulated by pregnancy. Pregnant patients with MS have been shown in retrospective studies to experience fewer exacerbations than non-pregnant historical controls and to have post-partum disease flares (Davis and Maslow, Obstet. Gynecol. Surv. 1992, 47, 290-296; Abramsky, O., Ann. Neurol. 1994, 36, S38-S41; Hutchinson, M., J. Neurol. Neurosurg. Psychiatry, 1993, 56, 1043-1045). Prospective studies of MS patients have confirmed the retrospective analyses (Bernardi et al., Acta Neurol. Scand. 1991, 84, 403-406; Birk et al., Arch. Neurol. 1990, 47, 738-742; Roullet et al., J. Neurol. Neurosurg. Psychiatry 1993, 56, 1062-1065; Sadovnik et al., Arch. Neurol. 1994, 51, 1120-1124). Furthermore, brain lesions in MS demonstrated by magnetic resonance have been shown to improve during pregnancy and return to the pre-pregnancy state in the postpartum period (van Walderveen et al., Neurology 1994, 44, 327-329) Like RA, MS has been treated with immunosuppressive drugs and more recent trials have included the use of monoclonal antibodies to T cell subsets, T cell receptors, cytokines, and adhesion molecules (Whitaker J. N., Ann. Neurol. 1994, 36, S103-S107; Utz and McFarland, J. Neuropath. Exp. Neurol. 1994, 53, 351-358). Recent studies demonstrate that a synthetic CD4 peptide analog inhibits experimental allergic encephalomyelitis (EAE) in a mouse model (Jameson et al., Nature 1994, 368, 744-746). Immunomodulation using both alpha- and beta-interferon have undergone clinical trials (Durelli et al., Neurology l994, 44, 406-413; Connelly, J. F., Ann. Pharmacother. 1994, 28, 610-616).
Spondyloarthropathies (HLA-B27 related diseases) are more common in males than in females. However, ankylosing spondylitis (AS), psoriatic arthritis (PS), and Reiter syndrome (RS) can affect women in the child-bearing age. Approximately 20% of patients suffering from the connective tissue disorder ankylosing spondylitis also experience remission of symptoms during pregnancy (Ostensen and Husby, "Seronegative spondylarthritis and ankylosing spondylitis: Biological effects and management", Pregnancy, Autoimmunity and Connective Tissue Disorders, edited by Scott, J. S. and Bird, H. A., Oxford Univ. Press, Oxford, N.Y., Tokyo, 1990, p. 163-184). In addition, while a systematic study of pregnancy effects on Psoriatic arthritis (PA) has not been reported, it is of interest that one of the pregnancy induced remission patients initially described by Hench in Mayo Clin. Proc. 1938, 13, 161-167 had PA.
In addition, the organ-specific autoimmune disease, Myasthenia gravis (MG), has been shown to have a variable response during pregnancy with about 30% of patients experiencing remission and 40% experiencing exacerbation (Varner, M. W., Semin. Perinatol. 1991, 15, 238-250; Plauche, W. C., Clin. Obstet. Gynecol. 1983, 26, 592-604).
The known phenomenon of pregnancy-induced remission and post partum exacerbation of rheumatoid arthritis (Persellin, RH, Bull. Rheum. Dis. 1976, 77, 922-927) led to the use of gamma globulin eluted from placentas in the treatment of rheumatoid arthritis. In one study, 11 patients were treated with placenta-eluted gamma globulin and improvement was noted in seven of these patients (Sany et al., Arthritis Rheum. 1982, 25, 17-24). High dose intravenous immunoglobulin (IVGG) has also been shown to be effective in modulating the course of rheumatoid arthritis (Tumiati et al., Arthritis Rheum. 1992, 35, 1126-1133). Ten patients with active, severe rheumatoid arthritis were treated with 6 monthly infusions. All patients showed improvement; however, all patients also relapsed within weeks of the last infusion.
It has now been found that treatment of patients with active rheumatoid arthritis by immunization with allogeneic MNC can result in amelioration of symptoms and improvement in disease activity indices. This treatment approach was taken in order to determine if the beneficial effects of pregnancy on these autoimmune diseases could be duplicated in non-pregnant patients. Treatment with allogeneic MNC can also be used in the treatment of a number of autoimmune disease, including, but not limited to, Multiple Sclerosis, Spondyloarthropathies, and Myasthenia Gravis.